Sadahira Y, Ruan F, Hakomori S, Igarashi Y
Biomembrane Institute, Seattle, WA 98119.
Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9686-90. doi: 10.1073/pnas.89.20.9686.
Sphingosine 1-phosphate (Sph-1-P), the initial product of Sph degradation by Sph kinase, was shown to be a strong inhibitor of cell motility and phagokinesis of B16 melanoma and other types of cells at 10-100 nM concentration. It also inhibited "chemoinvasion" of tumor cells through a thick layer of Matrigel on a filter membrane. Such inhibitory effects were produced minimally or not at all by Sph, N-methyl derivatives of Sph, or other related sphingolipids and phospholipids. Sph-1-P did not inhibit cell proliferation or protein kinase C (PKC) activity, in contrast to Sph and N-methyl-Sph, which inhibit PKC activity and cell growth in general. Radiolabeled [3H]Sph and [14C]N-methyl-Sph were rapidly incorporated into B16 melanoma cells. However, [14C]N-methyl-Sph was not metabolically converted into other compounds, whereas [3H]Sph was efficiently converted within 10 min to Sph-1-P, followed by conversion to other sphingolipids and phospholipids. The inhibitory effect of Sph-1-P on cell motility and tumor cell invasiveness could be a specific phenomenon independent of PKC and other known transmembrane signaling mechanisms, based on an unknown mechanism. It may directly affect organizational assembly of actin filaments. Since exogenous Sph is rapidly converted into Sph-1-P, some reported effects of Sph may be ascribable to such conversion.
鞘氨醇-1-磷酸（Sph-1-P）是鞘氨醇激酶降解鞘氨醇的初始产物，在浓度为10-100 nM时，它被证明是B16黑色素瘤及其他类型细胞的细胞运动和吞噬作用的强效抑制剂。它还抑制肿瘤细胞通过滤膜上的一层厚厚的基质胶进行“化学侵袭”。鞘氨醇、鞘氨醇的N-甲基衍生物或其他相关鞘脂和磷脂产生的这种抑制作用微乎其微或根本没有。与一般抑制蛋白激酶C（PKC）活性和细胞生长的鞘氨醇和N-甲基鞘氨醇不同，Sph-1-P不抑制细胞增殖或PKC活性。放射性标记的[3H]鞘氨醇和[14C]N-甲基鞘氨醇能迅速掺入B16黑色素瘤细胞。然而，[14C]N-甲基鞘氨醇不会代谢转化为其他化合物，而[3H]鞘氨醇在10分钟内可有效转化为Sph-1-P，随后再转化为其他鞘脂和磷脂。基于未知机制，Sph-1-P对细胞运动和肿瘤细胞侵袭性的抑制作用可能是一种独立于PKC和其他已知跨膜信号传导机制的特定现象。它可能直接影响肌动蛋白丝的组织组装。由于外源性鞘氨醇能迅速转化为Sph-1-P，一些报道的鞘氨醇的作用可能归因于这种转化。
